Glaucoma, one of the world's leading causes of visual impairment and blindness, is characterized by excavation of the optic nerve head and selective apoptotic loss of retinal ganglion cells (RGCs), resulting in a progressive decline in visual function. Nearly 67 million people worldwide are believed to have glaucoma, including an estimated 2.2 million in the USA. The etiology of the optic neuropathy is complex involving metabolic and biomechanical stress to the optic nerve head. The activation of astrocytes appears to have a central role in progressive optic neuropathy, serving as the cellular source of multifunctional cytokines and enzymes (matrix metalloproteinases [MMPs]) responsible for remodeling the extracellular matrix within the optic nerve head. In mammals, endogenous opioidergic peptides, such as enkephalins, dynorphins, and endorphins, are physiological modulators of neuroendocrine, immune, and inflammatory challenges that are released in response to stress. The effects of opioids are mediated through activation of three opioid receptor subtypes d, ?, and . Under stressful conditions (e.g., ischemic, oxidative, and inflammatory stress), endogenous opioidergic peptides are released reducing stress-related injuries. In addition, activation of opioid-receptors by an exogenous agonist has been shown to elicit a protective effect during the situations of stress. Preliminary data presented in this application provide concrete evidence that: 1) administration of morphine in a chronic ocular-hypertensive rat model protected functional and structural integrity of RGCs; 2) activation of opioid receptors by endogenous ligands is required for the development of neuroprotection induced by ischemic preconditioning; and 3) Morphine inhibits production of tumor necrosis factor-a (TNF-a) and MMP-2 from both the ocular hypertension and acute ischemia rat models. Based on the new preliminary data, I hypothesize that opioid-receptor activation protects the optic nerve head and retinal ganglion cells from injury, in part, by suppressing the production and activity of inflammatory cytokines from ONH astrocytes. To test this hypothesis, three specific aims are proposed: Specific Aim 1: Determine if activation of specific opioid-receptor subtypes promotes retina neuroprotection in a chronic ocular-hypertension rat model. Specific Aim 2: Identify the signaling pathways modulated by d-opioid-receptors in human ONH astrocytes for attenuation of TNF-a and MMP production. Specific Aim 3: Ascertain that activation of d-opioid-receptor protects the retina against glaucomatous injury by suppressing TNF-a and MMP activity within the optic nerve head. Outcomes of this project will provide valuable leads in the discovery of more effective therapies that can delay or prevent vision loss associated with neurodegenerative diseases such as glaucoma. 5